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- PDB-2aei: Crystal structure of a ternary complex of factor VIIa/tissue fact... -

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Basic information

Entry
Database: PDB / ID: 2aei
TitleCrystal structure of a ternary complex of factor VIIa/tissue factor and 2-[[6-[3-(aminoiminomethyl)phenoxy]-3,5-difluro-4-[(1-methyl-3-phenylpropyl)amino]-2-pyridinyl]oxy]-benzoic acid
Components
  • (Coagulation factor ...Coagulation) x 2
  • Tissue factor
KeywordsHYDROLASE / BLOOD COAGULATION / SERINE PROTEASE / THROMBOSIS / GLA / PYRIDINE / BENZAMIDINE / TISSUE FACTOR / COFACTOR / ENZYME INHIBITOR COMPLEX
Function / homology
Function and homology information


activation of plasma proteins involved in acute inflammatory response / activation of blood coagulation via clotting cascade / coagulation factor VIIa / response to Thyroid stimulating hormone / response to 2,3,7,8-tetrachlorodibenzodioxine / response to astaxanthin / response to thyrotropin-releasing hormone / response to genistein / serine-type peptidase complex / positive regulation of platelet-derived growth factor receptor signaling pathway ...activation of plasma proteins involved in acute inflammatory response / activation of blood coagulation via clotting cascade / coagulation factor VIIa / response to Thyroid stimulating hormone / response to 2,3,7,8-tetrachlorodibenzodioxine / response to astaxanthin / response to thyrotropin-releasing hormone / response to genistein / serine-type peptidase complex / positive regulation of platelet-derived growth factor receptor signaling pathway / response to vitamin K / response to carbon dioxide / response to thyroxine / NGF-stimulated transcription / response to cholesterol / response to growth hormone / positive regulation of positive chemotaxis / Extrinsic Pathway of Fibrin Clot Formation / positive regulation of leukocyte chemotaxis / cytokine receptor activity / positive regulation of TOR signaling / positive regulation of blood coagulation / animal organ regeneration / Gamma-carboxylation of protein precursors / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / Removal of aminoterminal propeptides from gamma-carboxylated proteins / positive regulation of endothelial cell proliferation / serine-type peptidase activity / BMAL1:CLOCK,NPAS2 activates circadian gene expression / positive regulation of interleukin-8 production / phospholipid binding / protein processing / cytokine-mediated signaling pathway / Golgi lumen / circadian rhythm / response to estrogen / positive regulation of angiogenesis / activation of cysteine-type endopeptidase activity involved in apoptotic process / blood coagulation / response to estradiol / collagen-containing extracellular matrix / protease binding / vesicle / response to hypoxia / positive regulation of cell migration / external side of plasma membrane / endoplasmic reticulum lumen / signaling receptor binding / serine-type endopeptidase activity / calcium ion binding / positive regulation of gene expression / cell surface / extracellular space / extracellular region / membrane / plasma membrane
Similarity search - Function
Tissue factor / Tissue factor, conserved site / Tissue factor signature. / Interferon/interleukin receptor domain / Interferon-alpha/beta receptor, fibronectin type III / Tissue factor / Peptidase S1A, coagulation factor VII/IX/X/C/Z / Coagulation factor-like, Gla domain superfamily / Coagulation Factor Xa inhibitory site / EGF-type aspartate/asparagine hydroxylation site ...Tissue factor / Tissue factor, conserved site / Tissue factor signature. / Interferon/interleukin receptor domain / Interferon-alpha/beta receptor, fibronectin type III / Tissue factor / Peptidase S1A, coagulation factor VII/IX/X/C/Z / Coagulation factor-like, Gla domain superfamily / Coagulation Factor Xa inhibitory site / EGF-type aspartate/asparagine hydroxylation site / EGF-like domain / EGF-like calcium-binding, conserved site / Calcium-binding EGF-like domain signature. / Aspartic acid and asparagine hydroxylation site. / EGF-like calcium-binding domain / Calcium-binding EGF-like domain / Vitamin K-dependent carboxylation/gamma-carboxyglutamic (GLA) domain / Gamma-carboxyglutamic acid-rich (GLA) domain / Gamma-carboxyglutamic acid-rich (GLA) domain superfamily / Vitamin K-dependent carboxylation domain. / Gla domain profile. / Domain containing Gla (gamma-carboxyglutamate) residues. / Epidermal growth factor-like domain. / EGF-like domain profile. / EGF-like domain signature 2. / EGF-like domain signature 1. / EGF-like domain / Fibronectin type III / Fibronectin type III superfamily / Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, histidine active site. / Serine proteases, trypsin domain profile. / Serine proteases, trypsin family, serine active site. / Trypsin-like serine protease / Serine proteases, trypsin domain / Trypsin / Trypsin-like serine proteases / Thrombin, subunit H / Immunoglobulins / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / Immunoglobulin-like fold / Immunoglobulin-like / Beta Barrel / Sandwich / Mainly Beta
Similarity search - Domain/homology
Chem-03R / CACODYLATE ION / Coagulation factor VII / Tissue factor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.52 Å
AuthorsAdler, M. / Whitlow, M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2005
Title: The discovery of fluoropyridine-based inhibitors of the Factor VIIa/TF complex.
Authors: Kohrt, J.T. / Filipski, K.J. / Cody, W.L. / Cai, C. / Dudley, D.A. / Van Huis, C.A. / Willardsen, J.A. / Rapundalo, S.T. / Saiya-Cork, K. / Leadley, R.J. / Narasimhan, L. / Zhang, E. / ...Authors: Kohrt, J.T. / Filipski, K.J. / Cody, W.L. / Cai, C. / Dudley, D.A. / Van Huis, C.A. / Willardsen, J.A. / Rapundalo, S.T. / Saiya-Cork, K. / Leadley, R.J. / Narasimhan, L. / Zhang, E. / Whitlow, M. / Adler, M. / McLean, K. / Chou, Y.L. / McKnight, C. / Arnaiz, D.O. / Shaw, K.J. / Light, D.R. / Edmunds, J.J.
History
DepositionJul 22, 2005Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 1, 2006Provider: repository / Type: Initial release
Revision 1.1Apr 30, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Non-polymer description / Version format compliance
Revision 1.3Aug 23, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_conn_type / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_conn_type.id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
L: Coagulation factor VII
H: Coagulation factor VII
T: Tissue factor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,40113
Polymers69,4113
Non-polymers99010
Water1,45981
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7150 Å2
ΔGint-88 kcal/mol
Surface area26410 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.215, 80.496, 125.936
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Coagulation factor ... , 2 types, 2 molecules LH

#1: Protein Coagulation factor VII / / Serum prothrombin conversion accelerator / SPCA / Proconvertin / Eptacog alfa


Mass: 17487.076 Da / Num. of mol.: 1 / Fragment: LIGHT CHAIN
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F7 / Organ (production host): kidney / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P08709, coagulation factor VIIa
#2: Protein Coagulation factor VII / / Serum prothrombin conversion accelerator / SPCA / Proconvertin / Eptacog alfa


Mass: 28103.256 Da / Num. of mol.: 1 / Fragment: HEAVY CHAIN
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F7 / Organ (production host): kidney / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P08709, coagulation factor VIIa

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Protein , 1 types, 1 molecules T

#3: Protein Tissue factor / / TF / Coagulation factor III / Thromboplastin / CD142 antigen


Mass: 23820.443 Da / Num. of mol.: 1 / Fragment: RESIDUES 33-243
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F3 / Production host: Saccharomyces cerevisiae (brewer's yeast) / References: UniProt: P13726

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Non-polymers , 4 types, 91 molecules

#4: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Ca
#5: Chemical ChemComp-CAC / CACODYLATE ION / dimethylarsinate / Cacodylic acid


Mass: 136.989 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6AsO2
#6: Chemical ChemComp-03R / 2-({6-{3-[AMINO(IMINO)METHYL]PHENOXY}-3,5-DIFLUORO-4-[(1-METHYL-3-PHENYLPROPYL)AMINO]-2-PYRIDINYL}OXY)BENZOIC ACID


Mass: 532.538 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H26F2N4O4
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 81 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.7 Å3/Da / Density % sol: 53.5 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5
Details: PEG 8000,CACODYLATE, GLYCEROL, pH 5.0, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1.08 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Feb 27, 1999
RadiationMonochromator: SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.08 Å / Relative weight: 1
ReflectionResolution: 2.52→20 Å / Num. all: 24709 / Num. obs: 21938 / % possible obs: 88.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.7 % / Rsym value: 0.11 / Net I/σ(I): 12
Reflection shellResolution: 2.52→2.63 Å / % possible all: 90

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Processing

Software
NameVersionClassification
MOSFLMdata reduction
SCALAdata scaling
MERLOTphasing
X-PLOR3.1refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1DAN USING SEPARATE REPLACEMENTS FOR EA

1dan


Resolution: 2.52→8 Å / Isotropic thermal model: OVERALL / σ(F): 2 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.297 759 3.9 %RANDOM
Rwork0.199 ---
all0.223 23642 --
obs0.204 21278 90 %-
Displacement parametersBiso mean: 28.2 Å2
Baniso -1Baniso -2Baniso -3
1--12.1723 Å20 Å20 Å2
2--5.2353 Å20 Å2
3---6.937 Å2
Refinement stepCycle: LAST / Resolution: 2.52→8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4679 0 52 81 4812
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.009
X-RAY DIFFRACTIONx_angle_deg1.802
X-RAY DIFFRACTIONx_improper_angle_d1.34
LS refinement shell

Refine-ID: X-RAY DIFFRACTION

Resolution (Å)Rfactor RfreeNum. reflection Rfree% reflection Rfree (%)Rfactor RworkNum. reflection RworkNum. reflection obs% reflection obs (%)
2.52-2.630.2718644.40.25291388145276.7
2.63-2.760.3183663.760.2521690175681.8
2.76-2.930.3054914.60.22881889198084.5
2.93-3.140.3222883.980.22042123221187.2
3.14-3.440.3301973.850.20132421251892.1
3.44-3.880.23771244.50.18492630275495.6
3.88-4.720.2581123.990.16092697280995
4.72-80.36171143.810.20652880299498.4

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